Level 1: Likely reliable evidence
The randomized placebo-controlled European Cooperative Acute Stroke Study III (ECASS III) evaluated alteplase (Activase, tissue-type plasminogen activator [t-PA]) in 821 patients aged 18-80 years with acute ischemic stroke (N Engl J Med. 2008;359:1317-1329). Alteplase 0.9 mg/kg (up to 90 mg) or placebo was given IV within 3-4.5 hours of non-severe stroke symptom onset. Exclusion criteria prior to randomization included severe stroke (NIH Stroke Scale score >25), brain hemorrhage, and major infarction. CT or MRI was performed 22-36 hours after treatment and again if clinically indicated. Protocol violations (did not receive treatment, did not meet age or imaging inclusion criteria, or received treatment outside the time window) occurred in 10.3% of alteplase and 11.9% of placebo patients. Thirteen (3.1%) alteplase patients and 10 (2.5%) placebo patients were lost to follow-up. The intention-to-treat analysis included all patients who violated protocol and who were lost to follow-up (using worst possible outcome).

At 90 days, a higher proportion of patients who received alteplase had disability score 0-1 on the modified Rankin scale (52.4% vs. 45.2%, P=.04, NNT 14). There were no significant differences in patients with disability score 2-3, disability score 4-5, or death.

Comparing alteplase vs. placebo, any intracranial hemorrhage occurred in 27% vs. 17.6% (P=.001, NNH 10). Risk of symptomatic hemorrhage varied based on definition; rates were 2.39% vs. 0.25% using the ECASS III definition (hemorrhage identified as predominant cause of neurologic deterioration) (P=.008, NNH 46) or 7.9% vs. 3.5% using the National Institute of Neurological Disorders and Stroke (NINDS) definition (suspicion of hemorrhage or any decline in neurologic status, and no hemorrhage on prior CT scan (P=.006, NNH 22). There were no significant differences in rates of fatal intracranial hemorrhage.

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While the results of this trial support a benefit for functional outcomes, this benefit is not necessarily supported by previous high-quality randomized trials. In the Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) randomized trial with 613 patients aged 18-79 years, alteplase given three to five hours after ischemic stroke onset increased the rate of symptomatic and fatal intracranial hemorrhage without apparent benefit in functional outcomes (JAMA. 1999;282:2019-2026). Based on another smaller randomized trial, t-PA given three to six hours after stroke onset does not appear beneficial and may increase mortality (Stroke. 2000;31:811-816).